tbuckley/cabot-search huggingface dataset:
Abstract 14621: The Endothelial Lipase Loss of Function Mutation R450G Causes Hyperalphalipoproteinemia That Does Not Protect Against ASCVD
Authors: Ali K Jaafar, Gilles Lambert
Journal: Circulation (2022)

Background: High-density lipoprotein cholesterol (HDL-C) levels and cardiovascular risk are inversely related in epidemiological studies. However, some rare monogenetic mutations that raise HDL do not appear to confer atheroprotection. Methods: The LIPG gene, encoding Endothelial Lipase (EL), was sequenced in 337 patients with hyperalphalipoproteinemia (HDL-C&gt;80mg/dL) for whom a causative variant in other genes affecting plasma HDL levels ( CETP, APOA1, ABCA1, LCAT, LPL, GALNT2 ) had been excluded. HDL particle size distribution was determined using a Lipoprint HDL subtraction test and further assessed by non-denaturing gradient gel electrophoresis followed by densitometric scanning. EL variants were cloned by site directed mutagenesis, expressed in HEK293 cells and compared to wild-type EL. Their expression in cell extracts and secretion in culture medium were measured by western-blot and ELISA. EL phospholipase enzymatic activity was assessed by measuring the production of non-esterified free fatty acids (FFA) using native and reconstituted HDL (rHDL) as substrates. Results: We identified the novel EL R450G missense mutation in three individuals (2 heterozygotes and one homozygote). Their HDL particles were larger than those of normolipemic controls (66±14% vs. 36±6% of large HDL1 particles; P=0.02). Six week treatment with Probucol 1g/day reduced the amount of HDL1 in those patients. Despite elevated circulating HDL levels, these patients presented with atherosclerotic cardiovascular disease. In vitro, the R450G variant was expressed and secreted normally from cells but displayed markedly reduced enzymatic activity compared with wild-type EL (Vmax = 6±4, vs. 32±5 nmol/Hr and Km = 0.01±0.07 vs. 0.30±0.15 mM, respectively; P&lt;0.01, all). Conclusion: EL-R450G is a loss-of-function variant associated with hyperalphalipoproteinemia. Carriers of this mutation do not appear to be protected against atherosclerosis.
Abstract 15285: Exercise Adherence Among Older Persons With Hiv: Characteristics and Performance
Authors: Crista Irwin, Rebecca Gary, Raphiel Murden, Melinda Higgins
Journal: Circulation (2022)

Introduction: Despite optimal treatment adherence, the inflammatory response associated with HIV remains, which leads to premature vascular aging and a heightened risk for cardiovascular disease (CVD). Persons with HIV (PWH) are twice as likely to develop CVD at an average of 8 years earlier than non-HIV infected persons. Routine aerobic exercise as recommended by the AHA guidelines has been shown to lower inflammation, reduce cardiovascular risk factors and to benefit overall health. AHA guidelines recommend moderate to vigorous physical activity (MVPA) of at least 150 minutes per week, but less than 50% of the general population meets this standard and little is known about these parameters in older PWH (OPWH). Hypothesis: The purpose of this study was to examine adherence to a moderate intensity exercise regimen among OPWH (n=76). Methods: All participants (mean age 55 +/- 5.2, 65% male, 82% Black) were evaluated at baseline (BL) for cardiorespiratory fitness and target HR using the modified Balke VO2 test. Participants were provided an exercise prescription based on their individual target HR at 60 - 70 % max for at least 240 minutes per week and provided with activity trackers to monitor exercise adherence. Each participant was remotely monitored at regular intervals using MI techniques to determine exercise intensity and adherence to exercise prescription. Results: Mean exercise adherence at 3-, 6-, and 12-months was 63%, 60% and 61% respectively. Higher adherence was associated with higher baseline VO 2 max and reported lower sleep disturbance, perceived stress, fatigue, and pain as well as greater emotional support throughout the study. Persons with higher adherence to exercise were also associated with greater improvement in vascular function measured by flow-mediated dilation at 6-months. Conclusions: OPLWH participating in an aerobic exercise program for 1 year consistently exceeded the recommended 150 minutes/week of moderate intensity exercise by 10+% more than the general population. Exercise adherent participants achieved a high degree of cardiovascular activity and a reduction in physical/emotional deterrents to exercise which may lead to reduced CVD risk.
Abstract 15319: Left Ventricular Assistant Device (lvad) Support Did Not Alter Mirna Expression in Heart Failure Patients
Authors: Kajari Dhar, Hesham Basma, John Um, Fang Qiu, Brian D Lowes
Journal: Circulation (2022)

Introduction: Micro RNAs (miRNA) are crucial regulators of various biological processes including the pathogenesis of heart failure (HF). In this study, miRNA profiling was compared with pre and post LVAD and non-failing (NF) control heart patients. Our goal was to identify miRNAs involved in HF and responses to LVAD therapy. Methods: Myocardial RNAs were isolated from non-ischemic dilated cardiomyopathy patients (n=22) who went through LVAD placement (pre LVAD) and later transplant (post LVAD) along with 6 normal hearts as controls. NanoString technology was used to quantify miRNA expressions. NanoString miRNAs raw count data were preprocessed and normalized using solver 4.0 Analysis Software. Ingenuity Pathway Analysis (IPA) was done by differentially expressed miRNA to understand the biological pathways involved. Results: Our sample population exhibited 80% male and 95% Caucasian with an average age of 57 and ejection fraction was less than 25% at the time of LVAD placement. The average LVAD duration of patients was 525 days. One ninety-five miRNAs in pre and 120 miRNAs in post LVAD patients were differentially expressed compared to control using cutoff of for the FDR adjusted p-value 0.05 and at least 2-fold changes. There was no significant change in miRNA expression when post LVAD was compared with pre LVAD patients. IPA analysis revealed that there are 15 up-regulated miRNA that promote apoptosis with a net Z score of 2.155 in post LVAD versus control. There are 27 miRNAs with a net of apoptotic with a Z score 0f 0.766 in pre LVAD versus control. It was also noticed from IPA analysis that expression of 8 identical miRNAs in both pre and post LVAD patients were involved in heart fibrosis. LVAD therapy did not change the miRNA expression Conclusions: Our results identify many miRNAs that are associated with apoptosis and fibrosis in end stage heart failure. Molecular mechanisms of heart disease will be identified by miRNA profiling and function as potential biomarkers or therapeutic targets in future. LVAD therapy does not substantially reverse these epigenetic changes in this population.
Abstract 15329: Heart Failure is an Adverse Risk Factor for Peri-Procedural Complications in Patients Undergoing Pulmonary Vein Isolation and Ablation for Atrial Fibrillation
Authors: Mouna Kodali, Ramtej Atluri, Sreeram Yalamanchili, Meghana Vallabhaneni, Mukunthan Murthi, Sujitha Velagapudi
Journal: Circulation (2022)

Introduction: Percutaneous catheter ablation (PCA) for non-valvular atrial fibrillation (AF) is rapidly becoming commonplace for recently diagnosed paroxysmal AF. Heart failure (HF) and AF commonly coexist in patients. Elevated left ventricular and atrial pressures result in progressive left atrial dilation and remodeling which in turn predisposes to the generation of AF. Since many who undergo PCA for AF could have HF, we aimed to assess peri-procedural outcomes in this population. Methods: We utilized the National Inpatient Sample from 2016-2019 to identify 74,205 hospitalized adults who underwent PCA for AF. These hospitalizations were further stratified based on the presence of HF. A multivariate regression model was used to adjust for confounders and analyze the variables. Results: Of those who underwent PCA for AF, 33,435 (45%) had HF. In-hospital mortality was higher in those with HF (1.9% vs 1.14%; p=0.0001). Figure 1 shows the Forrest plot for multivariate analysis of peri-procedural complications when adjusted for patient demographics, co-morbidities, and hospital characteristics. When adjusted similarly, patients with HF who underwent PCA for AF had longer length of stay (LOS) by 1.5 days (p&lt;0.001) and had additional hospital costs (HC) of $14,726 (p&lt;0.001). Conclusions: In this study, patients undergoing Percutaneous catheter ablation (PCA) for AF with co-existing acute HF had significantly worse end points in terms of in-hospital mortality, LOS, HC, atrial flutter, AKI, sepsis, pneumonia, endotracheal intubation. One major limitation of our study is the lack of outpatient follow up. Although outcomes are worse in the acute setting of HF, there have been several studies such as CASTLE-AF, outlining that early ablation for AF in HF is associated with positive long-term effects including lower rates of death and hospitalization for HF. Despite unfavorable peri-procedural outcomes of HF in PCA, the long-term benefits should not be overlooked.
Abstract 14610: Geographic Differences Among Patients With Acute Myocardial Infarction in the PARADISE-MI Trial
Authors: Jawad H Butt, David Sim, Brian Claggett, Karola Jering, peter van der meer, Prafulla Kerkar, Julio E Nuez Llota, Alberto Cadena, Mpiko Ntsekhe, Yinong Zhou, Lars Kober, John J McMurray, Marc A Pfeffer
Journal: Circulation (2022)

Introduction: The globalization of clinical trials has highlighted geographic differences in patient characteristics, treatments and outcomes, but there are few data on those with high-risk acute MI. We examined these differences in PARADISE-MI, the most globally representative trial in high-risk MI patients to date Methods: PARADISE-MI enrolled 5661 patients with an acute MI complicated by left ventricular dysfunction and/or pulmonary congestion; 23.0% were randomized in Eastern Europe/Russia (EER), 17.5% Western Europe, 12.2% Southern Europe, 10.1% Northern Europe (NE), 12.0% Latin America (LA), 9.3% North America (NA), 10.0% East/South-East Asia, 5.8% South Asia (SA) Results: Those from Asia, particularly SA, were notably different from patients enrolled in the other regions - they were younger, thinner and had a different pattern of comorbidities (high prevalence of diabetes despite lower BMI, and very low prevalence of AF), type of MI (more often STEMI) and treatment (low rate of primary PCI). By contrast, the characteristics of patients from LA did not differ meaningfully from those in Europe or NA. Use of ACEi/ARB (34.8%) and beta-blockers (65.5%) was remarkably low in SA, whereas MRA use was lowest in NA (21.8%) compared with the highest rate (53.0%) in EER. Rates of the primary composite outcome of cardiovascular death or incident HF varied two-fold among regions with the lowest rate in SA (4.6 / 100 person-years [PY]) and the highest in LA (9.2 / 100 PY). Strikingly, rates of incident HF varied almost six-fold among regions with the lowest rate in SA (1.0 /100 PY) and the highest in NE (5.9 /100 PY). Conversely, the rate of death from any cause varied about two-fold among regions (Figure) with the lowest rate in NA (2.4 /100 PY) and the highest in LA (5.3 / 100 PY) although the rate in the other six regions differed little (range 3.9 to 4.7 / 100 PY) Conclusion: In PARADISE-MI, there were substantial regional differences in patient characteristics, treatments and outcomes
Abstract 15843: Measures for Improving Health Equity in Pediatric Cardiology
Authors: Anna Harmeling, Michael Leonard, Alaina Kipps, Andrew Shin, Michal Palmon, Rebecca Kameny
Journal: Circulation (2022)

Background: Health inequity is an acknowledged clinical issue in pediatric cardiology with disparate outcomes for patients of difference races and ethic groups nationwide. Currently, there are no institutional real-time data dashboards to quantify local level inequities and target improvement projects. Goals Our aim was to determine metrics to measure patient outcomes and develop a health equity analysis tool to measure impact of future projects. Methods: This phase of the project was done in a three-step process. First, providers, administrators, and other stakeholders were surveyed to generate metric ideas. Next, PAC3 and PC4 Arbormetrix databases were utilized to note comparisons across institutions for these metrics. Finally, Lucile Packard Children's Hospital (LPCH) cardiac surgical data from 2017-2022 was used to determine metrics with statistical significance between groups of various demographic factors with standardization by procedure type, STAT category, and cardiopulmonary bypass time analysis. Results: Final metrics included postoperative length of stay (LOS), 30-day readmission rate, database discharge mortality, and hospital acquired complications. These were compared across race, ethnicity, Degauss scored socioeconomic status, and insurance type. For the most complex procedures (STAT category 5), LOS was nearly double for Hispanic vs. non-Hispanic patients (63 vs 34 days.) Additionally, Hispanic patients had a two-fold higher rate of 30-day readmission compared to non-Hispanic patients after pulmonary artery unifocalization surgery (8.0% vs. 4.0%) and 1.5-fold higher after VSD surgery (8.3% vs. 5.6%.) Conclusions: Utilizing these metrics, LPCH can efficiently note disparities in cardiac care and develop targeted solutions to mitigate them. Higher 30-day readmission rates, for example, may point to issues with health literacy or access. A final dashboard representing these metrics and analysis will be used by LCPH quality and improvement committees. Finally, further research and development will be done with partners at similar healthcare institutions regarding external validation and expansion.
Abstract 146: Risk Factors For Early Mortality After Fall From Height In An Urban Area
Authors: ANNA OZGULER, Arnaud Gille, Valentine Giorgetta, Michel Baer, Thomas Loeb
Journal: Circulation (2022)

Introduction: Death after falls from height are relatively common in urban areas. However, risk factors for early mortality are not clearly established, even fall height is still debated. The aim of this study was to identify risk factors for death on scene, after fall from a height, in patients aged 16 and over. Method: An Emergency Medical Service’s (EMS) database was used, it included all Advanced Life Support interventions. This EMS was located in an urban area with 300,000 inhabitants. All patients aged 16 and over, who fell from a height over 6.6 feet, between 2003 and 2018, were included. Age, gender, cause of fall (suicide or accidental), height of fall, landing surface (hard or soft), how the body hit the ground (headfirst landing or other), Index Severity Score (ISS) and initial Glasgow Coma Score (GCS) were collected. A backward stepwise logistic regression was used with occurrence of death on site as main outcome. Results: Six hundred and eighteen patients were included. The average age was 43.5 years (min 16-max 102) and sex ratio 2. Forty-eight percent were suicides. The average fall height was 36 feet (SD ± 35). The landing surface was hard in 51% of cases and landing was on head in 6%. The average ISS was 32 (SD ± 29.5) and mean GCS was 10 (SD ± 5.6). One hundred and ninety two (31%) patients died on scene. Results of the final logistic regression model are in table 1. Conclusion: In this study, age over 60, head first landing, suicide attempt, height of fall over 33 feet and hard landing surface, were significantly associated with on scene mortality after fall from height. Suicide prevention is one obvious way to reduce mortality from falls from heights.
Abstract 14737: Right Heart Remodeling After Pulmonary Valve Replacement in Patients With Pulmonary Atresia With Intact Ventricular Septum and Critical Pulmonary Stenosis
Authors: Margaret M Irwin, Lindsey Reynolds, Geoffrey Binney, Stuart Lipsitz, Sunil J Ghelani, David M Harrild, Chris Baird, Tal Geva, David W Brown
Journal: Circulation (2022)

Background: Patients with pulmonary atresia with intact ventricular septum (PA/IVS) and critical pulmonary stenosis (CPS) managed to a biventricular circulation may eventually require pulmonary valve replacement (PVR) for pulmonary regurgitation (PR). Right ventricular (RV) remodeling after PVR has been well described in tetralogy of Fallot (TOF); we sought to investigate RV volumetric and functional changes in PA/IVS using CMR. Methods: A retrospective cohort of PA/IVS and CPS patients who underwent PVR at Boston Children’s Hospital from 1995-2021 with CMR before and after PVR was matched 1:3 with TOF patients by age at PVR. Patients with initial intervention &gt;2 weeks of age or 1.5 ventricle circulation were excluded. Median regression modeling accounting for matching was performed with reduction in indexed right ventricular end diastolic volume (RVEDVi) post PVR as the primary outcome, adjusting for covariates including tricuspid regurgitation (TR) and PVR valve size. Results: Twenty PA/IVS or CPS patients (cases) were matched with 60 TOF (controls), with median age at PVR 14 years; at median follow-up 8 years post PVR, 95% were NYHA Class I. Pre-PVR RVEDVi was similar between groups (165 vs 167 ml/m 2 , p=0.7), although cases had higher RV EF (51.4 vs 48.6%, p=0.03), TR fraction (23 vs 9%, p=0.008), and a trend toward lower RV mass; PR fraction, LV volumes and EF were similar. Pre-PVR RV free wall and LV longitudinal strain were similar, although LV circumferential strain was worse in cases (-15.6 vs -17.1, p=0.01). At median 2 years after PVR, RVEDVi was similarly reduced from 166 to 118 ml/m 2 (p=0.73), although cases had higher RV EF (52.3% vs 46.9%, p=0.007) with less reduction in indexed RV mass (Δ4.5 vs 9.6 g/m 2 , p=0.02); LV volumes and EF were similar. Post PVR, RV and LV longitudinal strain remained unchanged both within and between groups; LV circumferential strain was similar post PVR and remained lower in cases vs controls. Conclusion: Patients with PA/IVS after PVR demonstrate similar RV remodeling to TOF patients, with lesser reduction in RV mass and comparatively better post RV EF. CMR strain imaging found no significant pre-post differences in RV or LV systolic parameters. Further investigation is needed to evaluate for changes in diastolic parameters.
Abstract 14740: Racial Disparities in Adverse Pregnancy Outcomes and Cardiovascular Health After Delivery: A Mediation Analysis in Numom2b-hhs
Authors: Lucia Petito, Xiaoning Huang, C. Noel Bairey Merz, Natalie A Bello, Janet Catov, Judith Chung, Abbi D Lane-Cordova, David Haas, Lisa D Levine, Rebecca McNeil, Eliza C Miller, George Saade, Lauren Theilen, Laura E Wiener, Lynn Yee, Philip Greenland, William Grobman, Sadiya S Khan
Journal: Circulation (2022)

Introduction: Racial disparities in risk of adverse pregnancy outcomes (APOs) and cardiovascular health (CVH) after delivery are well-established. Therefore, we sought to quantify the extent to which APOs explained racial differences in CVH. Methods: We included non-Hispanic (NH) Black and NH White individuals from the prospective, longitudinal nuMoM2b-HHS cohort. Race and ethnicity, which represent social constructs, were self-reported. APOs (hypertensive disorders of pregnancy [HDP], small for gestational age [SGA], preterm birth [PTB], and gestational diabetes mellitus [GDM]) were centrally adjudicated via medical records. The primary outcome was CVH score based on 4 metrics: body mass index, blood pressure, cholesterol, and glucose assessed at follow-up. Using a life-course approach, APOs were considered on the pathway between racial identity and CVH. Mean difference in CVH score was estimated via targeted maximum likelihood estimation (TMLE). Sensitivity analyses included alternative causal inference methods. All models were adjusted for age, study site, insurance, and fetal sex. Results: Among 2,987 birthing individuals, NH Black individuals were significantly more likely than NH White individuals to experience HDP, SGA, and PTB, and had lower (worse) CVH scores at follow-up (mean difference 0.52 [0.38-0.66]). Counterfactual disparity measures were estimated, which represent the adjusted racial difference in CVH score that would remain if no one experienced a particular APO ( Table ). Approximately 2% of the racial difference in CVH scores was due to racial differences in APOs when estimating with TMLE. Similar estimates were observed with other methods. Conclusions: A small proportion of the racial disparity in CVH years after delivery was mediated via APOs. Mitigating racial inequities in CVH will require interventions upstream of the first pregnancy (before an APO occurs) in addition to downstream risk factor control.
Abstract 14446: Bcl-x Short Isoform is Essential for Maintaining Multiple-Tissue Homeostasis
Authors: Mariko Keller, Michinari Nakamura
Journal: Circulation (2022)

Regulated cell death is an essential piece of normal development and maintenance of tissue homeostasis, wherein BCL2 like 1 (BCL2L1) protein is involved in key signaling pathways. Alternative splicing in exon 2 of Bcl2l1 produces Bcl-x short (Bcl-xS) isoform. However, mutations in around 5’ splice site are classified as variants of uncertain significance in humans, and the isoform-specific role of endogenous Bcl-xS remains largely unexplored. Here we show the role of Bcl-xS in vivo by generating the mice with a mutation in 5’ splice site of the Bcl2l1 that inhibits Bcl-xS alternative splicing. Although loss of BCL2L1 leads to embryonic lethal with massive cell death, Bcl-xS knockout (KO) mice were born at a mendelian ratio and showed no overt abnormality until 3 months of age. Thereafter, the KO mice developed cardiac hypertrophy (heart weight/tibia length, 8.59+/-0.308 vs 11.61+/-0.631, p = 0.0005 and 2.13-fold increase in individual cardiomyocyte size, p = 0.0001) with contractile dysfunction (EF, 69.25+/-1.31 vs 56.57+/-3.07, p = 0.0028) and splenomegaly (spleen weight/tibia length, 5.32+/-0.25 vs 7.12+/-0.49, p = 0.0051) at 6 months of age. Despite that overexpression of Bcl-xS induced cell death in cardiomyocytes (2.497-fold compared to LacZ, p &lt; 0.0001), there was unexpectedly no overt difference in the level of apoptosis in the KO heart (TUNEL, 0.033+/-0.003 vs 0.030+/-0.002 %, p = 0.359), but fibrosis was significantly increased in the KO heart (1.602+/-0.095 vs 2.340+/-0.145 %, p = 0.0017). Diabetes was not evident in the KO mice (blood glucose, 169.8+/-10.9 vs 153.3+/-8.46 mg/dl, p = 0.2595). Mechanistically, we found that the Akt/mTOR and JNK/cJun signaling are activated in the KO heart and the JNK/cJun signaling is activated with increased Bax expression in the KO spleen. These results suggest that Bcl-xS may be dispensable for development, but is essential for maintaining homeostasis of multiple organs, especially cardiosplenic network, in a tissue-dependent mechanism.